Osteoporosis and bone fractures are established complications of HIV/AIDS and two of every three patients with HIV-infection are osteopenic or osteoporotic leading to a fracture incidence up to 4 fold higher in HIV patients over a wide age range. This is especially pertinent to men where fracture risk is typically low until advanced age. This substantial increase in fracture prevalence in relatively young adults is a significant public health concern as fractures can be debilitating and are frequently associated with devastating outcomes. With the advancing age of this population due to the success of antiretroviral therapy (ART), a synergy between HIV- and age-related skeletal decline could precipitate an epidemic of bone fragility disease. Another major conundrum in this field is that ART exacerbates rather than ameliorates bone loss. Interestingly, the skeletal effects of ART, though varied in magnitude, appear universal regardless of regimen. While a wealth of data now supports the notion of ART-induced bone loss, exactly when after ART initiation bone resorption begins and abates is unclear, and the underlying mechanism remains enigmatic. This dearth of knowledge has handicapped the design and implementation of strategies to limit further bone loss in patients who already exhibit an impoverished skeleton resulting from direct HIV assault. To begin to explore these issues, we recently examined bone turnover in patients initiating ART and documented a surge in bone resorption in virtually all patients starting as early as 2 weeks after ART initiation, peaking by 12 weeks, and remaining significantly elevated for up to at least 24 weeks. Importantly, T-cell recovery with ART reaches a significant magnitude at 12 weeks, the same time point at which this surge in resorption peaked, suggesting a possible link between immune recovery and ART-induced bone loss. In fact, it is now well established that bone remodeling, the process responsible for skeletal renewal, is strongly influenced by the immune system. This is the result of a deep integration and centralization of common cell types and cytokine mediators that we have termed the immuno-skeletal interface. Based on our preliminary data demonstrating that T-cell reconstitution in animals elicits a rapid and robust bone loss and our clinical studies demonstrating a temporal relationship between ART initiation, immune-reconstitution, and bone resorption, we hypothesize that immune- reconstitution, a consequence of ART-induced disease reversal, leads to robust, but acute, bone loss during the early period of ART. We propose 2 Specific Aims to further address this hypothesis: Specific Aim 1: To elucidate the mechanisms by which T-cell reconstitution drives skeletal deterioration; and Specific Aim 2: To demonstrate that skeletal deterioration associated with ART in humans, is a rapid, but relatively acute event, associated with T-cell reconstitution and immune regeneration, as a consequence of ART-induced disease reversal. These mechanistic studies into the pathophysiology of ART-induced bone loss will set the stage for future clinical studies to explore therapeutic approaches to preventing ART-induced bone loss.